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Haploidentical (haplo-) donors and cord-blood (CB) stem cells provide alternative transplant options in patients lacking an HLA-matched donor. In case of relapse or graft failure after a first alternative allogeneic hematopoietic stem cell transplant (HSCT), a second alternative HSCT (HSCT2) is rarely considered due to a high risk of toxicity.A retrospective French multicentre study was performed, including patients with hematologic malignancies who underwent two consecutive HSCT from alternative donors. All data were exported from the national ProMISE database between 2000 and 2016.Forty-three patients (61.4%) received a CB-HSCT2 and 27 (38.6%) a haplo-HSCT2. Indications for HSCT were graft failure (51.4%) or disease progression (48.6%). Two-years probabilities of overall survival, progression-free survival and toxicity-related mortality were 18.5%, 17.8% and 55.8%, respectively. In multivariate analysis, complete remission status at HSCT2 and year of HSCT2 ≥ 2012 were significantly associated with a better outcome (with respectively hazard ratio [HR] = 0.42, p = .002 and HR = 0.5, p = .051).Neither the indication of HSCT2 nor the source of stem cell was more advantageous towards overall patient survival. A salvage haploidentical or cord-blood stem cell transplantation is a high-risk procedure, that may be considered for patients achieving a complete remission before receiving the second HSCT.

IntroductionAllogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to graft-versus-host disease (GvHD) and infectious complications. Alterations of the intestinal microbiota plays a major role in the development of allo-HSCT complications. The gut microbiota could be restored by faecal microbiota transplantation (FMT). However, there are no published randomised studies assessing the efficacy of FMT for GvHD prophylaxis.Methods and analysisThis prospective, open-label, multi-centre, parallel-group, randomised phase-II clinical trial has been designed to assess the effect of FMT on toxicity in patients treated with myeloablative allo-HSCT for haematological malignancy. Based on Fleming’s single-stage sample size estimation procedure, the design plans to include 60 male and female patients aged 18 or over per arm, to be randomly assigned to two groups, one with and one without (control group) FMT. The primary endpoint is GvHD-free relapse-free survival rate at 1 year after allo-HSCT. Secondary endpoints are outcome measures of the impact of FMT on allo-HSCT-related morbidity and mortality (overall survival and progression-free survival at 1 and 2 years, haematological parameters, infectious complications, tolerance and safety of FMT). The primary endpoint will be evaluated according to assumptions of the single-stage Fleming design, compared between groups by a log-rank test and further investigated in a multivariate marginal structural Cox model taking into account centre effect. The proportional-hazard hypothesis will be verified using Schoenfeld’s test and by plotting residuals.Ethics and disseminationThe local institutional review board (CPP Sud-Est II, France) issued approval on 27 January 2021. The French national authorities issued approval on 15 April 2021. The outcome of the study will be disseminated via peer-reviewed publications and at congresses.Trial registration numberNCT04935684.

Cytogenetic aberrations are found in 65% of adults and 75% of children with acute leukemia. Specific aberrations are used as markers for the prognostic stratification of patients. The current standard cytogenetic procedure for acute leukemias is karyotyping in combination with FISH and RT-PCR. Optical genome mapping (OGM) is a new technology providing a precise identification of chromosomal abnormalities in a single approach. In our prospective study, the results obtained using OGM and standard techniques were compared in 29 cases of acute myeloid (AML) or lymphoblastic leukemia (ALL). OGM detected 73% (53/73) of abnormalities identified by standard methods. In AML cases, two single clones and three subclones were missed by OGM, but the assignment of patients to cytogenetic risk groups was concordant in all patients. OGM identified additional abnormalities in six cases, including one cryptic structural variant of clinical interest and two subclones. In B-ALL cases, OGM correctly detected all relevant aberrations and revealed additional potentially targetable alterations. In T-ALL cases, OGM characterized a complex karyotype in one case and identified additional abnormalities in two others. In conclusion, OGM is an attractive alternative to current multiple cytogenetic testing in acute leukemia that simplifies the procedure and reduces costs.

Resume Introduction L’allogreffe de cellules souches hematopoietiques est la seule therapeutique curative pour de nombreuses hemopathies. Ce traitement peut donner lieu a des complications, notamment ophtalmologiques. Methodes Nous avons realise une revue de la litterature et nous avons etabli des recommandations accessibles et pratiques pour les hematologues et les ophtalmologues. Resultats Le suivi ophtalmologique doit etre systematique chez les patients ayant eu une allogreffe, par l’interrogatoire de l’hematologue et l’examen de l’ophtalmologue. Les complications liees a la reaction du greffon contre l’hote (GVHD) et non liees a la GVHD sont listees, ainsi que les differentes therapeutiques. Discussion Le depistage et le traitement des complications ophtalmologiques de l’allogreffe necessitent une collaboration etroite entre hematologues et ophtalmologues. La prise en charge par des soignants formes dans ce type de pathologie est recommandee.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can lead to early cardiac complications as well as late sequelae. A cardiac evaluation is essential in the pre-transplant assessment given the patient's comorbidities and previous chemotherapy treatments received. Various thresholds of cardiac function are recommended as eligibility criteria. The rise of haplo-identical transplantation with the use of post-transplant high-dose cyclophosphamide (PT-Cy) as a prophylaxis against graft-versus-host disease (GVHD) is accompanied by a resurgence of cardiological concerns. Arrhythmias are also a concern and the list of drugs implicated in this complication is growing. The rare occurrence of cardiac GVHD has been reported, although the entity is not well defined. Finally, although long-term follow-up recommendations exist, they are not accompanied by specific targets for cardiovascular risk factors, the presence of which is nevertheless increased after HSCT. In the framework of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) practice harmonization workshops held in Lille in September 2019, the prophylaxis, the diagnostic approach and the treatments of cardiac complication following HSCT were reviewed after analysis of published studies.

International audience; Stomatological complications of allogeneic hematopoietic stem cell transplantation (HSCT) are frequent and very uncomfortable for patients. The primary complication is the graft versus host disease reaction. Other side effects of the procedure include infections, taste disorders and carcinogenic risks. Various local treatments are used but remain imperfect. Within the framework of the 10th workshop of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2019, diagnostic approaches and treatments of tongue and oral complications following allogeneic HSCT were reviewed according to the analysis of published studies.

Stomatological complications of allogeneic hematopoietic stem cell transplantation (HSCT) are frequent and very uncomfortable for patients. The primary complication is the graft versus host disease reaction. Other side effects of the procedure include infections, taste disorders and carcinogenic risks. Various local treatments are used but remain imperfect. Within the framework of the 10th workshop of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2019, diagnostic approaches and treatments of tongue and oral complications following allogeneic HSCT were reviewed according to the analysis of published studies.

Allogeneic stem cell transplantation is currently the only curative therapy for hematological disorders. This treatment can lead to complications, of which ophtalmological involvement.We reviewed the literature and established accessible and convenient recommendations for hematologists and ophthalmologists.Ophtalmological follow-up should be done in every patient having had an allogeneic transplantation, by the hematologist questioning and by the ophthalmologist physical exam. Complications due to graft-versus-host disease (GVHD) or not due to GVHD are cited, as well as therapeutic options.Screening and treatment of ophthalmologic complications in allogeneic stem cells transplantation recipients requires a close collaboration between hematologists and ophthalmologists. The management of these patients by caregivers trained in these questions is encouraged.

Allogeneic hematopoietic stem cell transplantation is one of the most efficient curative treatment for acute leukemia. But it is also a heavy process with an important risk of complications, particularly infection and graft versus host disease. Increasing data in literature show that an alteration of the intestinal microbiota of allogeneic stem cell recipients is associated with these complications. Indeed, treatments used during conditioning regimen lead to an impaired microbiota, which cannot fulfill its protective functions anymore. To limit this microbiota impairment, we could restore a healthy microbiota by a fecal microbiota transplantation, which has already shown its efficiency in the treatment of Clostridium difficile infection. The aim of this review is to describe the intestinal microbiota, the link between microbiota and complications of allogeneic stem cells transplantation, and the recent published data on fecal microbiota transplantation in this field.

Allogeneic hematopoïetic stem cell transplantation is one of the most efficient curative treatment for acute leukemia. But it is also a heavy process with an important risk of complications, particularly infection and graft versus host disease. Increasing data in literature show that an alteration of the intestinal microbiota of allogeneic stem cell recipients is associated with these complications. Indeed, treatments used during conditioning regimen lead to an impaired microbiota, which cannot fulfill its protective functions anymore. To limit this microbiota impairment, we could restore a healthy microbiota by a fecal microbiota transplantation, which has already shown its efficiency in the treatment of Clostridium difficile infection. The aim of this review is to describe the intestinal microbiota, the link between microbiota and complications of allogeneic stem cells transplantation, and the recent published data on fecal microbiota transplantation in this field.

International audience

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

Ibrutinib is a new-targeted therapy that irreversibly and specifically inhibits the Bruton's Tyrosine Kinase (BTK), a key component of the signaling pathways of B cells. The results are very encouraging as monotherapy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Following the results of recent studies, ibrutinib is now available in France for these three diseases.

The oncogenic role of TCL1 in chronic lymphocytic leukemia is well established in transgenic mice. TCL1 expression in other B-cell malignancies has been also described: post-germinal center-derived malignancies, such as multiple myeloma, classically do not express TCL1. Waldenström macroglobulinemia is a post-germinal center malignancy that is known to be similar to chronic lymphocytic leukemia in terms of its gene expression profile. TCL1 expression has not been so far assessed in Waldenström macroglobulinemia. Transcriptomic explorations show that TCL1A expression is linked to signaling pathways and biological functions that are known to be involved in Waldenström macroglobulinemia as well as to gene signatures of interest in B-cell malignancies. We investigated TCL1 expression at the protein level in the bone marrow of a series of 59 patients with Waldenström macroglobulinemia: 76% of patients expressed TCL1, which appeared to be associated with a pejorative prognostic impact. TCL1 could have an oncogenic role in Waldenström macroglobulinemia, and deserves further exploration.

International audience; INTRODUCTION: Malnutrition is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is a well-known prognostic factor for survival. The nutritional status of patients in a long term after allo-HSCT is less well documented. The main objective of this study was to evaluate the prevalence of malnutrition in adult patients who underwent allo-HSCT more than one year ago. Secondary objectives were to assess body composition, muscle strength, and factors associated with malnutrition. PATIENTS & METHODS: All allo-HSCT patients admitted into the University Hospital of Clermont-Ferrand between 1st January 1985 and 31st December 2012 were screened. Clinical and biological nutritional assessments included anthropometric measurements, serum nutritional proteins, body composition assessed by bioelectrical impedance, and upper-limb muscle strength (MS) measured by dynamometry. Hematological and nutritional data during and after hospital stay for allo-HSCT were retrospectively collected. RESULTS: Eighty four allo-HSCT patients (52% men; mean age 54.4 +/- 12.5 years) were enrolled. Average follow-up after allo-HSCT was 56.4 +/- 47.5 months. Prevalence of malnutrition at the end of follow-up was 20%. Compared to well-nourished patients (WN group), undernourished patients (UN group) at the end of follow-up were significantly more likely to be undernourished (50% vs. 21%, p = 0.04) at hospital admission, and to have a Nutritional Risk Index of

Resume La rechute reste la premiere cause de mortalite des hemopathies malignes apres allogreffe de cellules souches hematopoietiques (allo-CSH) (van den Brink et al., 2010). Le risque de recurrence de la maladie est eleve chez les patients presentant des marqueurs cytogenetiques ou moleculaires de mauvais pronostic, et/ou allogreffes en situation de maladie refractaire ou en remission hematologique sans reponse moleculaire ou radiologique (TEP-scan) complete. Dans le cadre des 7e ateliers d’harmonisation des pratiques de greffe de la Societe francophone de greffe de moelle et de therapie cellulaire (SFGM-TC), le groupe de travail s’est base sur les donnees de la litterature, afin d’elaborer des recommandations concernant la prevention et le traitement de la rechute post allo-CSH. Pour les LAM et les SMD a haut risque, une strategie de maintenance post-greffe est possible par des agents hypomethylants ou des ITK anti-FLT3 si la cible est presente. En ce qui concerne les LAL Phi+, un traitement de maintenance par ITK est un consensus. Pour les lymphomes, il n’existe pas a l’heure actuelle des donnees formelles concernant l’utilisation d’un traitement de maintenance systematique et une strategie preemptive basee sur l’immunomodulation, le suivi du chimerisme et l’injection des lymphocytes du donneur est recommandee. Pour le myelome multiple, meme si l’indication de l’allogreffe reste discutee, notre recommandation serait l’utilisation d’un traitement de maintenance par bortezomib, vue la bonne tolerance de ce traitement, sans augmentation du risque de GVHD.

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in acute myeloid leukemia (AML) patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory hematological malignancies or with persistent molecular or radiological (PET-CT scan) residual disease. For high risk AML and myelodysplasia (MDS), a post transplant maintenance strategy is possible, using hypomethylating agents or tyrosine kinase inhibitors (TKI) anti-FLT3 when the target is present. For Philadelphia positive acute lymphoblastic leukemia (ALL), there is a consensus for the use of TKI anti BCR-ABL as post transplant maintenance.

Plasma cell leukemia (PCL) is a rare disorder which develops spontaneously (primary PCL) or evolves in patients with multiple myeloma (secondary PCL). It is defined by the presence of 2 × 10(9)/L peripheral blood plasma cells or plasmacytosis accounting for more than 20 % of the differential white cell count. PCL presents more often extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, as well as impaired renal function. Cytogenetic abnormalities and mutations observed in PCL lead to escape from immune surveillance and independence from the bone marrow microenvironment with changes in expression of adhesion molecules or chemokines receptors. The outcome of PCL has improved with combination approaches with novel agents (including bortezomib and immunomodulatory drugs, such as lenalidomide) and with autologous stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is currently available for young patients. This article is an overview of this rare and severe disease and the different therapeutics options that are recommended.

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.

Ruxolitinib is a JAK/STAT inhibitor, which has demonstrated clinical benefits in patients with intermediate-2 and high-risk myelofibrosis. Moreover, first results of recent clinical trials show a trend to better overall survival with ruxolitinib, which allows to hope that we will soon be able to change the natural evolution of this poor outcome disease. With such results, ruxolitinib quickly obtained the Food and Drug Administration (FDA) approval in the United States of America. In France, ruxolitinib is now available, allowing its administration to symptomatic myelofibrosis patients.

Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed.

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

International audience; BACKGROUND: The impact of antithymocyte globulin (ATG) in the setting of a myeloablative conditioning transplantation remains controversial, especially when using bone marrow (BM) as the stem cell source. METHODS: We therefore conducted a retrospective analysis to investigate the impact of ATG in patients with acute myeloid leukemia or myelodysplastic syndrome receiving myeloablative conditioning followed by a matched 10 of 10 unrelated donor transplant from BM or peripheral blood stem cells (PBSCs). Our study included 356 patients conditioned with cyclophosphamide associated with fractionated total body irradiation or busulfan. RESULTS: Median follow-up was 17.6 months (range, 0-156). The ATG and PBSCs were the only variables that independently decreased the cumulative incidence (CI) of chronic graft-versus-host disease (GvHD) (hazards ratio [HR], 0.4; 95% CI, 0.21-0.73; P \textless 0.01; and HR, 0.53; 95% CI, 0.30-0.90; P = 0.02, respectively). The ATG had no impact on overall survival, disease-free survival, relapse, and nonrelapse mortality. In the PBSC group (n = 139), ATG was associated with a lower CI of both grades III to IV acute GvHD (HR, 0.17; 95% CI, 0.03-0.91; P = 0.04), chronic GvHD (HR, 0.31; 95% CI, 0.11-0.87; P = 0.03), and GvHD-free/relapse-free survival (HR, 0.48; 95% CI, 0.29-0.80; P \textless 0.01), whereas these correlations were not significant in the group of patients (n = 217) receiving BM (HR, 0.36; 95% CI, 0.11-1.93; P = 0.06 for grade III-IV acute GvHD; HR, 0.49; 95% CI, 0.22-1.06; P = 0.08 for chronic GvHD; and HR, 0.69; 95% CI, 0.46-1.01; P = 0.06 for GvHD-free/relapse-free survival). CONCLUSIONS: Although our results confirm the recommendation for ATG to be added after PBSC transplantation, no obvious benefit was identified using this approach in the setting of BM transplantation. Only prospective studies may yield definitive answers to this question

Oncogenesis is correlated with the occurrence of multiple genomic events allowing cancer cells to acquire new properties, including the capacity of survival and proliferation with down regulated control signals. Among those genomic events, the study of recurrent translocations, particularly common in oncohematology, has allowed for a better understanding of leucemogenesis and lymphomagenesis mechanisms. These translocations are classically distinguished depending on their physiopathologic consequences. It may encode for a fusion gene leading to a chimeric protein, which exhibits a new activity or an aberrant one, corresponding in most cases to the constitutive activation of a proto-oncogene. In other cases, these translocations may cause abnormal expression of a proto-oncogene with a regular structure by a transcriptional deregulation. Beyond this highlighting recurrent translocations and understanding better the physiopathologic consequences of these chromosomal modifications has a real impact on patients. These cytogenetic anomalies represent an essential diagnostic tool for some hematologies; and pave the way for a better evaluation of the prognosis and thus, a better adaptation of the therapeutic strategy. They also contributed to improve survival with the development of targeted therapies. Finally, thanks to cytogenetic techniques combined to molecular biology techniques, cytogenetic aberrations can be used as a marker of response, which allowed a monitoring of residual disease.

Histone deacetylases inhibitors (HDACi) represent a new epigenetic targeting therapy class, which is widely investigated in fundamental research and clinical trials. They are able to restore and increase tumor suppressor genes expression and to play an anti-tumoral activity through numerous targets, which are distributed all over the main differentiation, proliferation and survival cellular pathways. Their use in hematology led to vorinostat (SAHA) and romidepsin approval by FDA for the treatment of refractory cutaneous T-cell lymphomas. Preclinical and preliminary clinical results show a promising antineoplasic activity in most hematologic malignancies. This review will focus on the HDACi recent developments and current investigations, highlighted by recent communications.

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.

Pulmonary involvement with multiple myeloma is rare. We report the case of a 61-year-old man with past medical history of chronic respiratory failure with emphysema, and a known multiple myeloma (Durie and Salmon stage III B and t(4;14) translocation). Six months after diagnosis and first line of treatment, he presented acute dyspnea with interstitial lung disease. Computed tomography showed severe bullous emphysema and diffuse, patchy, multifocal infiltrations bilaterally with nodular character, small bilateral pleural effusions, mediastinal lymphadenopathy, and a known lytic lesion of the 12th vertebra. He was treated with piperacillin-tazobactam, amikacin, oseltamivir, and methylprednisolone. Finally, outcome was unfavourable. Postmortem analysis revealed diffuse and nodular infracentimetric infiltration of the lung parenchyma by neoplastic plasma cells. Physicians should be aware that acute respiratory distress syndrome not responding to treatment of common causes could be a manifestation of the disease, even with negative BAL or biopsy and could be promptly treated with salvage therapy.

Introduction. Chronic lymphocytic leukemia (CLL) has typically an indolent course but can undergo transformation into a more aggressive lymphoma (mainly of diffuse large B-cell lymphoma histology) that is called Richter's syndrome. While the advent of novel therapies targeting the BCR signaling or the BCL-2 protein is transforming the management of patients with CLL, these drugs failed to prevent the risk of RS that is estimated to be 0.5-1% per year. RS is associated with a very poor outcome and is thus becoming the main obstacle to long term CLL cure. Allogeneic stem-cells transplantation (allo-SCT) has been recommended as the treatment of choice in eligible patients with clonally related RS (Rossi Blood 2018) but previous experience is still limited to less than 50 cases. We here aimed to investigate the safety and efficacy of allo-SCT for patients with RS. Methods. We report on a retrospective study of consecutive patients with RS who underwent allo-HSCT between 2005 and 2016 in 15 French and Belgian centers from the Société Francophone de Greffe de Moelle et de Transplantation Cellulaire (SFGM-TC). Inclusion criteria were: age >18, confirmed RS diagnosis, allo-HCST from either sibling or unrelated donor. Data quality was ensured using computerized discrepancy errors and on-site data verification. Results. A total of 24 patients (median age=59 years [19-69], M/F= 18/6) were included in the present study. Median time from CLL to RS diagnosis was 59 months [0-198]. The histology was DLBCL (86%) or HL (14%). The patients received a median of 1 [0-4] therapeutic line for CLL and 1 [0-3] for RS. Nine (38%) patients underwent auto-SCT prior to allo-HCT. At allo-HCT, 17 (71%) of patients were in complete and 7 (29%) in partial response. Most patients received reduced intensity conditioning (RIC) regimen (n= 18, 75%) and peripheral blood (76%) as source of stem-cells. Two (8%) patients received bone marrow stem cells and 4 (16%) cord blood stem cells. Donors were related (n=8) or unrelated (mismatched, n=8; matched, n=5; missing, n=3). A total of 15 patients (63%) received total body irradiation (TBI) within the conditioning. With a median follow-up of 27 months, 2-year OS was 44% (figure 1). The 100-day non-relapse mortality was 25%. Cause of death was relapse (n=3), treatment toxicity (n=10; GVHd, n=3; infectious complications, n=6; pulmonary toxicity, n=1), infection complications (n=1) and cerebral stroke (n=1). 2-year OS was significantly shorter for older patients (20% if >59 years old vs 64% if ≤59,P = 0.031). The 2-year OS was influenced by presence of cGVHD (73% vs 25%,P = 0.006). Neither donor type, prior auto-SCT, disease status prior to allo-HCT, use of antilymphocyte serum infusions nor the regimen conditioning significantly impact OS. Conclusion. Our study suggests that allo-HCT is a strategy achieving prolonged survival but should be performed in young patients to limit the risk of NRM. The favorable impact of GVHd suggests an anti-RS allogenic effect. Disclosures Guieze: abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Ibrutinib is a new-targeted therapy that irreversibly and specifically inhibits the Bruton's Tyrosine Kinase (BTK), a key component of the signaling pathways of B cells. The results are very encouraging as monotherapy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström's macroglobulinemia. Following the results of recent studies, ibrutinib is now available in France for these three diseases.

Background Myeloablative allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a major procedure usually accompanied by multifactorial malnutrition, prompting the recommendation of systematic artificial nutritional support. Parenteral nutrition (PN) is usually administered during allo-HSCT, essentially for practical reasons. Recently published data suggest that enteral nutrition (EN), given as systematic artificial nutrition support, could decrease grade III–IV graft-versus-host disease (GVHD) and infectious events, which are associated with early toxicity after allo-HSCT and then have an impact on early transplant-related mortality (D100 mortality). Methods/Design We report on the NEPHA trial: an open-label, prospective, randomised, multi-centre study on two parallel groups, which has been designed to evaluate the effect of EN compared to PN on early toxicity after an allo-HSCT procedure. Two hundred forty patients treated with allo-HSCT for a haematological malignancy will be randomly assigned to two groups to receive either EN or PN. The primary endpoint will assess the effect of EN on D100 mortality. Secondary endpoints will compare EN and PN with regards to the main haematological, infectious and nutritional outcomes. Discussion The impacts of nutritional support should exceed the limits of nutritional status improvement: EN may directly reduce immunological and infectious events, as well as decrease early transplant-related morbidity and mortality. EN and PN need to be prospectively compared in order to assess their impacts and to provide treatment guidelines. (Clinical trials gov number: NCT01955772; registration: July 19th, 2013).

Low molecular weight heparins (LMWH) are commonly used in the ICU setting for thromboprophylaxis as well as curative decoagulation as required during renal replacement therapy (RRT). A rare adverse event revealing immunoallergic LMWH induced thrombopenia (HIT) is skin necrosis at injection sites. We report the case of a patient presenting with skin necrosis witnessing an HIT after RRT, without thrombocytopenia. The mechanism remains unclear. Anti-PF4/heparin antibodies, functional tests (HIPA and/or SRA), and skin biopsy are of great help to evaluate differential diagnosis with a low pretest probability 4T’s score.

Introduction et but de l’etude La denutrition est frequente et constitue un facteur pronostique de survie chez les patients avec allogreffe de cellules souches hematopoietiques (allo-CSH). Sa prise en charge constitue un enjeu majeur. Les objectifs de cette etude etaient d’evaluer la prevalence de la denutrition a distance d’une allo-CSH chez des patients adultes, la composition corporelle, la force musculaire (FM) et les facteurs associes a une denutrition a distance. Materiel et methodes Un screening des patients allogreffes depuis plus de 6 mois dans un service d’hematologie adulte a ete effectue. Une evaluation nutritionnelle (poids, IMC, albumine, transthyretine, FM au membre superieur par dynamometrie et impedancemetrie) a ete realisee avec un recueil retrospectif des donnees hematologiques et nutritionnelles a l’entree, pendant et a la sortie d’hospitalisation pour l’allo-CSH. Resultats et analyse statistique Quatre-vingt-quatre patients (hommes 52 % ; âge moyen 54,4 ± 12,5 ans) ont ete inclus . Le delai moyen post-allo-CSH etait de 56,4 ± 47,5 mois. La prevalence de la denutrition a distance de l’allo-CSH, evaluee sur la perte de poids, l’IMC et les proteines nutritionnelles, etait de 20 % (dont 4 % de denutrition severe). Compares aux patients non denutris (groupe ND), les patients denutris a distance (groupe D) avaient significativement plus souvent, a l’entree en hospitalisation, une denutrition (50 % vs. 21 %, p = 0,04) et un NRI p = 0,004). La FM etait significativement plus souvent diminuee dans le groupe D (24 % vs. 3 %, p = 0,005). L’index de masse musculaire (IMM) etait diminue chez 30,5 % des patients et l’index de masse musculaire appendiculaire (IMMSA) chez 36,6 %, sans difference entre D et ND. Cette diminution etait plus frequente chez les femmes que chez les hommes (IMM : 45 % vs. 16,6 %, p p p = 0,07). En analyse multivariee, aucun facteur n’etait significativement associe a une denutrition a distance, mais le statut denutri a l’entree en hospitalisation tendait a majorer ce risque (OR = 3,60 [0,95 ; 13,67], p = 0,06). Conclusion La denutrition, consequence frequente de l’allo-CSH, peut se retrouver plusieurs mois, voire annees, apres l’allo-CSH, et ce d’autant plus frequemment qu’elle existe deja avant l’allo-CSH. Ces resultats soutiennent l’objectif d’une prise en charge nutritionnelle specialisee precoce pour amener les patients en bon etat nutritionnel a l’allo-CSH.

Plasma cell leukemia (PCL) is a rare disorder which develops spontaneously (primary PCL) or evolves in patients with multiple myeloma (secondary PCL). It is defined by the presence of 2 × 10(9)/L peripheral blood plasma cells or plasmacytosis accounting for more than 20 % of the differential white cell count. PCL presents more often extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, as well as impaired renal function. Cytogenetic abnormalities and mutations observed in PCL lead to escape from immune surveillance and independence from the bone marrow microenvironment with changes in expression of adhesion molecules or chemokines receptors. The outcome of PCL has improved with combination approaches with novel agents (including bortezomib and immunomodulatory drugs, such as lenalidomide) and with autologous stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is currently available for young patients. This article is an overview of this rare and severe disease and the different therapeutics options that are recommended.

Ruxolitinib is a JAK/STAT inhibitor, which has demonstrated clinical benefits in patients with intermediate-2 and high-risk myelofibrosis. Moreover, first results of recent clinical trials show a trend to better overall survival with ruxolitinib, which allows to hope that we will soon be able to change the natural evolution of this poor outcome disease. With such results, ruxolitinib quickly obtained the Food and Drug Administration (FDA) approval in the United States of America. In France, ruxolitinib is now available, allowing its administration to symptomatic myelofibrosis patients.

Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed.

Oncogenesis is correlated with the occurrence of multiple genomic events allowing cancer cells to acquire new properties, including the capacity of survival and proliferation with down regulated control signals. Among those genomic events, the study of recurrent translocations, particularly common in oncohematology, has allowed for a better understanding of leucemogenesis and lymphomagenesis mechanisms. These translocations are classically distinguished depending on their physiopathologic consequences. It may encode for a fusion gene leading to a chimeric protein, which exhibits a new activity or an aberrant one, corresponding in most cases to the constitutive activation of a proto-oncogene. In other cases, these translocations may cause abnormal expression of a proto-oncogene with a regular structure by a transcriptional deregulation. Beyond this highlighting recurrent translocations and understanding better the physiopathologic consequences of these chromosomal modifications has a real impact on patients. These cytogenetic anomalies represent an essential diagnostic tool for some hematologies; and pave the way for a better evaluation of the prognosis and thus, a better adaptation of the therapeutic strategy. They also contributed to improve survival with the development of targeted therapies. Finally, thanks to cytogenetic techniques combined to molecular biology techniques, cytogenetic aberrations can be used as a marker of response, which allowed a monitoring of residual disease.

Histone deacetylases inhibitors (HDACi) represent a new epigenetic targeting therapy class, which is widely investigated in fundamental research and clinical trials. They are able to restore and increase tumor suppressor genes expression and to play an anti-tumoral activity through numerous targets, which are distributed all over the main differentiation, proliferation and survival cellular pathways. Their use in hematology led to vorinostat (SAHA) and romidepsin approval by FDA for the treatment of refractory cutaneous T-cell lymphomas. Preclinical and preliminary clinical results show a promising antineoplasic activity in most hematologic malignancies. This review will focus on the HDACi recent developments and current investigations, highlighted by recent communications.

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.

Background: A recent prospective study (Socie & al Blood 2011) demonstrated that the addition of antithymocyte globulins (ATG) to prophylaxis for graft versus host disease (GVHD) in the setting of standard myeloablative conditioning (MAC) regimen matched unrelated donor (UD) allogeneic stem cell transplantation (HSCT) resulted in a decrease in incidence of chronic GVHD without an increase of relapse or non-relapse mortality. However, stem cell source was mostly peripheral blood stem cells (PBSC) and patients (pts) were compatible at HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 (eight out of eight alleles). A retrospective study using the same setting (Mohty & al Leukemia 2012) found very similar results with donor/recipient pairs matched at 10 loci (ten out of ten alleles). However, one third of the pts received PBSC as stem cells source and 20% of the pts were transplanted with a mismatch donor (9 out of 10 alleles). We thus conducted this study to assess the impact of ATG in pts with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted with MAC using bone marrow only (BM) from matched 10/10 UD. Patients and methods: We includedall consecutive pts older than 18 years who received a first HSCT in France for AML or MDS with BM from a matched 10/10 UD after a standard conditioning regimen (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=106 or Endoxan-Cy, n=91) between June 2000 and June 2012. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). This study was approved by the scientific committee of the SFGM-TC. Results: A total of 197 adult pts met the criteria and were analyzed (165 AML (84%) and 35 MDS). 54 (27%) pts received ATG in the conditioning regimen whereas 143 (73%) did not. Median follow up was of 20.3 months [0.4-156]. Both groups (with or without ATG) were well balanced except for the number of CD34+ cells infused (higher in the ATG group: 3.07x106/kg [0.7-13] vs 2.71x106/kg [0.6-89] for none ATG group (p=0.03)) and GvHD prophylaxis (more likely cyclosporine plus methotrexate with ATG (94%) vs 84% without, p=0.05). The probability of acute GvHD grade II-IV was similar between both groups: 41.3% with ATG vs 49.6% without, p=0.2. Incidence rate of severe acute GVHD grade III-IV at day 100 tended to be lower in the ATG group as compared with the none ATG group (20.3% vs 9.5%, respectively, p=0.052). The cumulative incidence (CI) of chronic GVHD at 2 years was 42% in the ATG group vs 28% in the none ATG group and 37% vs 44% at 4 years, respectively (p=0.18). The probability of extensive chronic GVHD at 2 years was identical between both groups (12% with ATG vs 16% without, p=0.95). CI of non-relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, advanced disease status was the only parameter associated with decreased DFS (HR 0.37, 95% CI [0.19-0.70], p=0 .02) and OS (HR 0,41, 95% CI [0,24;0,71], p

Background Waldenström's macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by a lymphoplasmacytic infiltration of the bone marrow (BM) and a serum monoclonal IgM. WM tumor cells show variable differentiation, ranging from mature B-cells to plasma cells. T-cell leukemia/lymphoma 1 (TCL1) is a small non-enzymatic protein normally expressed only during the early stages of lymphopoiesis and known to be a coactivator of AKT and of the NF-KappaB transcription pathway. TCL1 is up-regulated and plays a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL) since transgenic mice expressing TCL1 in B cells developed an aggressive form of CLL (Bichi et al., PNAS 2002). Moreover high TCL1 expression level is linked to aggressive features and poor outcome in CLL. TCL1 was also shown to be expressed in various B-cell lymphomas but not in multiple myeloma (Weng et al., Blood 2012). TCL1 might also have a potential role in the pathogenesis of WM but TCL1 expression is not so far described in WM. Aim We proposed to assess the expression pattern of TCL1 and its potential prognostic value in WM. Methods Firstly, we checked the TCL1A expression in WM by conducting an analysis using NCBI’s GEO2R tool of publically available transcriptomic data which compared gene expression profiling of CLL (n=11), MM (n=12) and WM patients (B-lymphocyte (BL) (n=10) and plasma cell (PC) (n=10)) (GSE6691 from NCBI’s GEO database, Gutiérrez et al. Leukemia 2007). Secondly, we performed histological and immunostaining analyses for TCL1 on deparaffinized whole tissue contiguous sections of 57 WM patients’ BM trephine biopsies (median age: 62 years, sex ratio M/F: 36/21, symptomatic: n=36, previously treated: n=10). Diagnostic and treatment criteria for WM fulfilled recommendations of the 2nd international WM workshop. TCL1 immunostains were graded independently by three investigators on a 4-tier scoring which had previously been used to study TCL1 in CLL (Herling et al., Leukemia 2006). TCL1 immunostains intensity was scored as follows: 1- low intensity, 2- middle intensity, 3- strong intensity; tumor infiltration patterns were defined as interstitial, nodular and interstitial, nodular or diffuse and tumor infiltration percentage was assessed according to CD20 immunostains. Results The analysis of transcriptomic data revealed that TCL1A expression level in WM is significantly higher than those found in MM and lower than those found in CLL (Figure 1). Immunohistochemistry analysis of BM showed that TCL1 protein was expressed in 45 patients (79%), with an intratumoral heterogeneous repartition and its localization appeared mostly cytoplasmic. Pattern of expression was: negative (n=12), less than 5% of tumor cells positive (n=6), positive in up to 50% of tumor cells (n=15), and positive in over 50% of tumor cells (n=24). TCL1 pattern was correlated neither with tumor infiltration pattern nor grading. TCL1 seemed not to be associated with any prognostic factors and TCL1+ and TCL1- patients were comparable in terms of clinical and lab features as for ISS. Median follow-up was 50 months. Among the 21 asymptomatic WM patients, median time to first treatment was 33 months for TCL1+ group, while none of TCL1- patients needed so far any first line therapy (p=0.24). Among the patients requiring treatment, we did not observe any impact of TCL1 expression level on ORR (63% for TCL1+ and 67% for TCL1- patients, p=0.85). TCL1+ patients presented a trend for a poorer 3 year-PFS than TCL1- patients (32% versus 62% respectively, p=0.15). Median time to next treatment (TTNT) was only 24 months for TCL1+ patients and not reached for TCL1-patients (p=0,079) (Figure 2). Median OS was 94 months in the whole population without clear influence of the TCL1. Disclosures: No relevant conflicts of interest to declare.

Objectives Allogeneic hematopoietic stem cell transplantation (AHSCT) is an effective treatment modality for a number of hematological malignancies. Several retrospective studies demonstrate that the addition of antithymocyte globulin (ATG) to standard GvHD prophylaxis in myeloablative conditioned AHSCT resulted in a reduction of the incidence of acute and chronic GvHD. However the impact of rabbit ATG incorporated within a standard myeloablative conditioning regimen (MAC) prior to AHSCT on overall survival (OS) has never been clearly assessed. The purpose of this study is to evaluate retrospectively the long term influence of ATG on OS in a large cohort. Methods All AHSCT with matched sibling donor (MSD) and matched unrelated donor (MUD) performed between 2001-2010 in France and reported to Promise database were retrospectively studied. Patients fulfilling the requirements for this study had received a MAC such as total body irradiation (TBI)-cyclophosphamide or busulfan-cyclophosphamide (Bu-Cy) with or without ATG. Results 1980 AHSCT were reported in 32 transplant centers. One hundred and fifty (8%) patients received ATG (25 with MSD and 125 with MUD), whereas 1830 (92%) did not receive ATG (1441 with MSD and 389 with MUD). Diagnosis were 1452 acute leukemia (73%), 340 myelodysplasia (MDS) and/or myeloproliferative syndrome (MPS) (17%), 157 lymphoma (8%), 9 myeloma and 21 chronic lymphocytic leukemia (CLL) (2%). 1385 patients received a TBI 12 Gy based regimen with cyclophosphamide whereas 595 patients received Bu-Cy. Bone marrow (1468 patients) or peripheral blood stem cells (512 patients) were infused 24-48h after the last cyclophosphamide administration (day 0). Median age at transplantation was 37.5 years in the ATG group and 39.2 years in the non ATG group. Median follow-up was of 79.8 months [19.2-138.8]. Using multivariable analysis, OS was adversely significantly influenced by age of recipient older than 39.1 years, bone marrow stem cell source, MUD, non-complete remission status before HSCT, GvHD grade 2-4, age of donor older than 38.3 years and the use of GvHD prophylaxis other than cyclosporine and methotrexate. ATG was not an independent variable influencing OS. The use of different model of multivariate analyses including propensity score trends to demonstrate that the influence of ATG on OS remain strongly correlated to donor type (MSD vs MUD). According to our results, patient with MSD presented better OS (not reached) than patient with MUD (37 months) (p Conclusion The use of ATG does not influence OS. However, this use is strongly influenced by stem cell source with a negative impact of ATG for the group of patients who received BM. Its usefulness should be discussed. Disclosures: No relevant conflicts of interest to declare.

Abstract 4576 Introduction Allo-HSCT procedure is associated with a frequent and potentially severe malnutrition which could highly participate to the transplant-related morbidity (TRM). Optimal nutritional management is still poorly known while both enteral nutrition (EN) and parenteral nutrition (PN) are effective. We proposed to retrospectively evaluate the impact of EN versus PN as nutritional support on early outcome of allo-HSCT. Patients and methods We retrospectively analyzed all the successive patients who needed a nutritional support during their first allo-HSCT in our center from January 2009 to October 2010, excepting whose who had a progressive disease at time of transplant. Datas were compared in an intent to treat analysis according the EN or PN initial nutritional support strategy. Results We analysed early outcome of 56 successive patients. Twenty of them received a myeloablative conditioning regimen and 36 a reduced intensity one. A total of 28 agreed to receive EN via a nasogastric feeding tube and the remaining 28 received PN. No significant difference in terms of age, diagnosis, disease status at transplant, conditioning regimens, stem cell source, GVHD nor antifungal secondary prophylaxis could be observed between the EN and PN groups. We found a lower median duration of fever in EN (2[0–8] vs. 5[0–17] (days); p=0.0026) and a lower need for antifungal therapy in EN group (7/28 vs. 17/28; p=0.0069), with a lower median duration of intravenous antifungal use (0 day [0–99] in EN vs. 7 days [0–93] in PN; p=0.00034) while incidence of bacteriemiae was not different. We observed a lower rate of replacement of central veinous catheter in EN group (3/28 in EN vs. 9/28 in PN; p=0.05) and a lower rate of transfer to ICU in the EN group (2/28 in EN vs. 8/28 in PN, p=0.036) but early death rate ( Conclusion Compared with PN, EN directly decreases the infectious risk, particularly the fungal risk, and its complications in allo-HSCT, without influencing hematopoietic toxicity nor GVHD incidence. Based on these encouraging results, we are now conducting a prospective, multicentric and randomized trial to confirm EN benefice in allo-HSCT. Disclosures: No relevant conflicts of interest to declare.